The overall aim of this project is to identify genes, primarily through genome-wide RNAi screens and cDNA library over-expression, that can act as potential drug targets to promote the survival of organisms irradiated with a dose of irradiation capable of destroying their hematopoetic system. We will probe different aspects of survival in response to IR including direct survival, resistance to oxidative stress, the control of hematopoetic stem cell proliferation and differentiation, and apoptosis control. We will also screen for chemicals that disrupt the major known checkpoint pathway known to cause killing in response to IR and for inhibitors of proteins identified in our RNAi screens, in order to identify molecules that can prolong survival after exposure to ionizing radiation. We will investigate the pathways involved in radio-resistance genetically and chemically with the goal of finding drugs and drug targets that will promote survival of people who have undergone potentially lethal irradiation.